PROJECT SUMMARY New approaches for curative treatments could substantially reduce the numbers of individuals living with HIV- 1, thus diminishing the need for life-long adherence to ART. However, solutions must include clearing infection and preventing latent reservoirs. While ART is the standard of care for HIV+ individuals, the field has not yet addressed an alternative to ART therapy that could halt infection and halt virus expansion. A proven nonhuman primate (NHP) model for infection that examines new therapeutic regimens that can be instituted very soon after virus exposure, or in cases of viral control under ART, is needed to address whether it is possible to eradicate HIV. With the discoveries of extremely potent and broad antibodies that target multiple determinants on the HIV-1 Envelope, a cure strategy is now recognized as an attainable goal. The overall goal of this project is to design Fc function-enhanced anti-HIV-1 human monoclonal antibodies (mAbs) and test them for virus eradication in rhesus macaques in a Clade C, Tier 2, SHIV post-exposure protection model. Anti-viral functions mediated by the Fc part of the molecule are crucial to antibody protection against HIV, but clearing HIV-1 infection using antibodies is a new paradigm for antibodies. Specific combinations of neutralizing mAbs have been predicted to have the potential for neutralization coverage against large cross-clade panels of HIV-1 isolates; V2-directed mAbs were identified as an immune correlate of RV144 in reducing infection risk. Our working hypothesis is that combinations of mAbs, if enhanced for antibody-dependent cellular cytotoxicity (ADCC), phagocytosis (ADCP), and complement activation, and engineered and tested in vivo for increased half-life, would be extremely effective in ablating early acute infection and limiting or eliminating seeding of viral reservoirs. The project proposal outlines a research plan to engineer, develop and characterize in vitro a panel of human monoclonal anti-HIV mAbs with enhanced effector function designed to increase the effectiveness of killing HIV-1 infected cells. Fc regions of mAbs of known potency and breadth will be modified by site directed mutagenesis for increased effector functions and for optimal affinity to human and macaque Fc?Rs. Once modified, functional assays will be used to evaluate the improvements in ADCC, ADCP and complement activation. Increased half-life evaluations will be performed in NHP. Combinations of modified mAbs will be tested in vitro to identify the most optimal groupings for additive effect of neutralization and effector functions. These mAbs will be chosen for large-scale production in amounts and purity needed for macaque experiments. An iterative progression of post-infection studies will be conducted in rhesus macaques, testing several combinations and examining doses and varying intervals before treatment. The practical goal is to formulate the most optimal combinations of mAbs that provide the highest degree of viral and reservoir clearance.